PROJECT SUMMARY Benign prostatic hyperplasia (BPH) is the most common cause of bothersome lower urinary tract symptoms (LUTS) in men affecting half by age 50 and about 90% of men by age 80. BPH is characterized by hyperplastic growth of glandular epithelial cells and fibromuscular stromal cells, leading to enlargement of the median and lateral lobes of prostate. The resulting bladder outlet obstruction impedes the flow of urine through the prostatic urethra, accounting for the development of LUTS (urgency, frequency, weak stream, straining, hesitancy, intermittency and night time voiding). Although current surgical management of BPH is efficacious, the increasing age and morbidity of this patient population has resulted in considerable clinical need for equally effective but less invasive and less morbid procedures. Histotripsy is an emerging noninvasive technology that applies short, high-amplitude focused ultrasound pulses to mechanically disintegrate tissue. Histotripsy is being investigated for a variety of diseases, including benign prostate hyperplasia, thrombosis, tumor treatment, and congenital defects. Investigations of the technology have strongly focused on soft tissues that are primarily cellular; the bioeffects, imaging and gross signatures of tissue breakdown, histological analysis, exposure parameters, and other aspects of the treatment are characterized and progressed based on the response of soft, glandular tissues. However, many of these diseases including BPH contain a critical fibrous component. Preliminary data indicates that different histotripsy exposures can achieve either fibrous tissue sparing or ablation. In this proposal, we aim to characterize the physical and biological effects of histotripsy on fibrotic tissue, evaluate promising treatment strategies to treat such tissue, and apply these methods specifically to improve histotripsy of the prostate. We propose to develop physical and numerical models for bubble-fibrous matrix interaction and characterize the physical effects of histotripsy exposures on fibrous structures using ultrasound and optical imaging methods. New exposure strategies will be tested to promote disintegration of fibrous tissue and identification of tissue disruption via ultrasound imaging feedback. Advanced strategies will be tested in ex vivo human prostate specimens to confirm improved ablation. Acute and chronic bioeffects will be assessed in a canine model of BPH. We will also measure changes in voiding patterns and urodynamics between treatment groups to demonstrate symptomatic improvement. The successful implementation of this project will overcome existing obstacles to clinical implementation of histotripsy for BPH and aid development of histotripsy for other applications.